Nucleobases substituted by a perfluoroalkyl group are important compounds as medical drugs and intermediates for medical and agricultural chemicals, and nucleobases having a trifluoromethyl group are particularly useful compounds. Therefore, many studies have been conducted on processes for producing the trifluoromethyl-substituted nucleobases.
With respect to a method for producing 5-trifluoromethyl uracil which is important as an intermediate for an anticancer agent, an antiviral agent, or the like, for example, Patent Document 1 discloses a method for producing 5-trifluoromethyl uracil by reacting 5-trifluoromethyl-5,6-dihydrouracil which is obtained by a reaction of α-trifluoromethyl acrylic acid and urea, with dimethyl sulfoxide and iodine in the presence of concentrated sulfuric acid as a catalyst. Furthermore, Patent Document 2 discloses a method of reacting 5-iodouracils with copper iodide and methyl fluorosulfonyldifluoroacetate to convert them to a 5-trifluoromethyluracils. Moreover, Patent Document 3 discloses a method for producing 5-trifluoromethyluracil, in which thymine is chlorinated with a chlorine gas to form 2,4-dichloro-5-trichloromethylpyrimidine, and then fluorinated with anhydrous hydrofluoric acid or antimony trifluoride in the coexistence with antimony pentachloride, followed by a treatment with water.
However, these methods have problems that all the methods include multi-steps and the last method uses anhydrous hydrofluoric acid and the antimony compound which are industrially hard to handle. Moreover, Non-patent Document 1 discloses a method for trifluoromethylating 3′,5′-diacetyl-2′-deoxyuridine at the 5-position with trifluoroacetic acid and xenon difluoride. However, this method also uses a special reagent and is industrially hard to employ.
Furthermore, with respect to a method for producing 5-trifluoromethylcytosine, Non-patent Document 2 discloses a method for producing 5-trifluoromethylcytosine by hydrolyzing 4-amino-2-chloro-5-trifluoromethylpyrimidine obtained by a reaction of 2,4-dichloro-5-trifluoromethylpyrimidine and liquid ammonia, and treating it with an ion-exchange resin. However, this method has a problem of multi-steps including production of raw materials.
With respect to a method for producing a purine compound having a trifluoromethyl group, for example, Non-patent Document 3 discloses a method for producing 8-trifluoromethyladenine, 2,6-diamino-8-trifluoromethylpurine and 8-trifluoromethylhypoxanthine by reacting 4,5-diaminopyrimidines with trifluoroacetic acid or trifluoroacetic anhydride. Non-patent Document 4 discloses a method for producing 8-trifluoromethylguanine by reacting 2,4-diamino-5-trifluoroacetamino-6-oxo-1,6-dihydropyrimidine, which is obtained by a reaction of 2,4,5-triamino-6-oxo-1,6-dihydropyrimidine and trifluoroacetic acid, with trifluoroacetic anhydride. However, all of these methods also industrially have a problem of multi-steps including production of raw materials.
With respect to direct perfluoroalkylation of these nucleobases, for example, Patent Document 4 discloses a method for producing purines having a perfluoroalkyl group at the 8-position or 2-position by reacting purines with N,O-bis(trimethylsilyl)trifluoroacetamide in the presence of pyridine and trimethylchlorosilane as catalysts and then reacting the resultant with bis (perfluoroalkyl)peroxide. However, this method has problems that it uses di(haloacyl)peroxide which is industrially hard to handle, that it uses a chlorofluorocarbon solvent and that it forms regioisomers with the substituent at the different positions. Furthermore, non-patent Documents 5 and 6 disclose a method for producing 5-perfluorobutyluracil, 8-perfluorobutylhypoxanthine and an 8-perfluorobutylxanthine salts by the formation of a uracil anion electrochemically, followed by the reaction with perfluorobutyl iodide. However, this method has problems that it uses the electrochemical technique which is industrially hard to use and that the resulting product is a salt of a supporting electrolyte.
Non-patent Document 7 discloses a method for producing 8-trifluoromethylcaffeine by reacting 8-trifluoromethyltheophylline obtained by a reaction of 5,6-diamino-1,3-dimethyluracil and trifluoroacetic anhydride, with potassium carbonate and methyl iodide in N,N-dimethylformamide. However, this method industrially has a problem of multi-steps including production of raw materials.
With respect to perfluoroalkylation with a perfluoroalkyl halide, Non-patent Document 8 discloses a method for obtaining trifluoromethylnucleosides by reacting 2′,3′,5′-tri-O-acetylated iodonucleosides with copper powder and trifluoromethyl iodide in hexamethylphosphoric triamide to obtain a 2′,3′,5′-tri-O-acetylated trifluoromethylnucleosides, and followed by deprotecting them. However, this method also has problems of multi-steps and use of hexamethylphosphoric triamide which is industrially hard to use.
Moreover, Non-patent Documents 9 and 10 disclose a process using perfluorobutyl iodide or perfluoropropyl iodide which is liquid at room temperature, through the use of dimethyl sulfoxide, hydrogen peroxide and iron (II) sulfate. However, substrates are restricted to pyrroles, indoles and substituted benzenes. Furthermore, there is no description with respect to trifluoromethylation using a perfluoroalkyl halide which is gas at room temperature, for example, trifluoromethyl iodide.    Patent Document 1: JP-A-2001-247551    Patent Document 2: JP-A-11-246590    Patent Document 3: JP-A-6-73023    Non-patent Document 1: Journal of Organic Chemistry, Vol. 53, pp. 4582-4585, in 1988    Non-patent Document 2: Journal of Medicinal Chemistry, Vol. 13, pp. 151-152, in 1970    Non-patent Document 3: Journal of the American Chemical Society, Vol. 80, pp. 5744-5752, in 1957    Non-patent Document 4: Justus Libigs Annalen der Chemie, Vol. 726, pp. 201-215, in 1969    Patent Document 4: JP-A-5-1066    Non-patent Document 5: Tetrahedron Letters, Vol. 33, pp. 7351-7354, in 1992    Non-patent Document 6: Tetrahedron, Vol. 56, pp. 2655-2664, in 2000    Non-patent Document 7: Journal of Medicinal Chemistry, Vol. 36, pp. 2639-2644, in 1993    Non-patent Document 8: Journal of the Chemical Society, Perkin Transaction 1, pp. 2755-2761, in 1980    Non-patent Document 9: Tetrahedron Letters, Vol. 34, No. 23, pp. 3799-3800, in 1993    Non-patent Document 10: Journal of Organic Chemistry, Vol. 62, pp. 7128-7136, in 1997